Hypertrophic cardiomyopathy: Genetics, pathogenesis, clinical manifestations, diagnosis, and therapy

Circulation Research

Volumn 121, Issue 7, 2017, Pages 749-770

  Marian, Ali J ^a,b   Braunwald, Eugene ^c  

^a UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^b TEXAS HEART INSTITUTE   (United States)

^c HARVARD MEDICAL SCHOOL   (United States)

Author keywords

Cardiac; Cardiomyopathy; Death; Heart failure; Human; Hypertrophic; Mutation; Myosin heavy chains; Sudden

Indexed keywords

BETA ADRENERGIC RECEPTOR BLOCKING AGENT; BX 1514M; CALCIUM CHANNEL BLOCKING AGENT; CARDIOVASCULAR AGENT; CYCLOSPORIN; DILTIAZEM; DISOPYRAMIDE; DIURETIC AGENT; ELECLAZINE; ENALAPRIL; MYOSIN BINDING PROTEIN C; MYOSIN HEAVY CHAIN BETA; PERHEXILINE; PIRFENIDONE; RANOLAZINE; TRIMETAZIDINE; UNCLASSIFIED DRUG; VALSARTAN; VERAPAMIL; GENETIC MARKER;

ADOLESCENT; ADULT; ARTICLE; ATRIAL FIBRILLATION; CLINICAL FEATURE; DISEASE ASSOCIATION; DISEASE COURSE; DISEASE SEVERITY; FAINTNESS; FAMILY; FAMILY HISTORY; FIBROSING ALVEOLITIS; GENE IDENTIFICATION; GENE MUTATION; GENETIC SCREENING; GENETICS; HEART LEFT VENTRICLE EJECTION FRACTION; HEART LEFT VENTRICLE HYPERTROPHY; HEART LEFT VENTRICLE OUTFLOW TRACT OBSTRUCTION; HEART VENTRICLE TACHYCARDIA; HIGH RISK PATIENT; HISTOPATHOLOGY; HUMAN; HYPERTROPHIC CARDIOMYOPATHY; INTERVENTRICULAR SEPTUM; LEFT VENTRICULAR DIASTOLIC DYSFUNCTION; MOLECULAR PATHOLOGY; MUSCLE CELL; MUSCLE HYPERTROPHY; MYBPC3 GENE; MYH7 GENE; PATHOGENESIS; PRIORITY JOURNAL; PROGNOSIS; RISK FACTOR; SUDDEN CARDIAC DEATH; YOUNG ADULT; ANIMAL; BIOPSY; CARDIAC IMAGING; CARDIAC MUSCLE; CARDIOMYOPATHY, DILATED; DNA MUTATIONAL ANALYSIS; GENETIC MARKER; GENETIC PREDISPOSITION; HEART LEFT VENTRICLE FUNCTION; MOLECULAR DIAGNOSIS; MUTATION; PATHOLOGY; PATHOPHYSIOLOGY; PHENOTYPE; PREDICTIVE VALUE; RISK ASSESSMENT;

ANIMALS; BIOPSY; CARDIAC IMAGING TECHNIQUES; CARDIOMYOPATHY, DILATED; DNA MUTATIONAL ANALYSIS; GENETIC MARKERS; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MOLECULAR DIAGNOSTIC TECHNIQUES; MUTATION; MYOCARDIUM; PHENOTYPE; PREDICTIVE VALUE OF TESTS; PROGNOSIS; RISK ASSESSMENT; RISK FACTORS; VENTRICULAR FUNCTION, LEFT;

EID: 85030619064     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.117.311059     Document Type: Article

References (250)

1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation. 1995;92:785–789.
2. Maron BJ, Mathenge R, Casey SA, Poliac LC, Longe TF. Clinical profile of hypertrophic cardiomyopathy identified de novo in rural communities. J Am Coll Cardiol. 1999;33:1590–1595.
3. Hada Y, Sakamoto T, Amano K, Yamaguchi T, Takenaka K, Takahashi H, Takikawa R, Hasegawa I, Takahashi T, Suzuki J. Prevalence of hypertrophic cardiomyopathy in a population of adult Japanese workers as detected by echocardiographic screening. Am J Cardiol. 1987;59:183–184.
4. Zou Y, Song L, Wang Z, Ma A, Liu T, Gu H, Lu S, Wu P, Zhang dagger Y, Shen dagger L, Cai Y, Zhen double dagger Y, Liu Y, Hui R. Prevalence of idiopathic hypertrophic cardiomyopathy in China: a population-based echocardiographic analysis of 8080 adults. Am J Med. 2004;116:14–18.
5. Authors/Task Force Members, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, McKenna WJ, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the task force for the diagnosis and management of hypertrophic cardiomyopathy of the european society of cardiology (ESC). Eur Heart J. 2014;35:2733–2779. doi: 10.1093/eurheartj/ehu284.
6. Charron P, Dubourg O, Desnos M, Isnard R, Hagege A, Millaire A, Carrier L, Bonne G, Tesson F, Richard P, Bouhour JB, Schwartz K, Komajda M. Diagnostic value of electrocardiography and echocardiography for familial hypertrophic cardiomyopathy in a genotyped adult population. Circulation. 1997;96:214–219.
7. Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, McKenna W, Kristinsson A, Roberts R, Sole M, Maron BJ, Seidman JG, Seidman CE. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med. 1998;338:1248–1257. doi: 10.1056/NEJM199804303381802.
8. Bick AG, Flannick J, Ito K, et al. Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts. Am J Hum Genet. 2012;91:513–519. doi: 10.1016/j.ajhg.2012.07.017.
9. Maron BJ, Peterson EE, Maron MS, Peterson JE. Prevalence of hypertrophic cardiomyopathy in an outpatient population referred for echocardiographic study. Am J Cardiol. 1994;73:577–580.
10. Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2015;65:1249–1254. doi: 10.1016/j.jacc.2015.01.019.
11. Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG, Seidman CE. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation. 2002;105:446–451.
12. Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ, Elliott PM. Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation. 2002;105:1407–1411.
13. Seo J, Kim M, Hong GR, Kim DS, Son JW, Cho IJ, Shim CY, Chang HJ, Ha JW, Chung N. Fabry disease in patients with hypertrophic cardiomyopathy: a practical approach to diagnosis. J Hum Genet. 2016;61:775–780. doi: 10.1038/jhg.2016.52.
14. Chimenti C, Pieroni M, Morgante E, Antuzzi D, Russo A, Russo MA, Maseri A, Frustaci A. Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy. Circulation. 2004;110:1047–1053. doi: 10.1161/01.CIR.0000139847.74101.03.
15. Greaves SC, Roche AH, Neutze JM, Whitlock RM, Veale AM. Inheritance of hypertrophic cardiomyopathy: a cross sectional and M mode echocardiographic study of 50 families. Br Heart J. 1987;58:259–266.
16. Branzi A, Romeo G, Specchia S, Lolli C, Binetti G, Devoto M, Bacchi M, Magnani B. Genetic heterogeneity of hypertrophic cardiomyopathy. Int J Cardiol. 1985;7:129–138.
17. Hartmannova H, Kubanek M, Sramko M, Piherova L, Noskova L, Hodanova K, Stranecky V, Pristoupilova A, Sovova J, Marek T, Maluskova J, Ridzon P, Kautzner J, Hulkova H, Kmoch S. Isolated X-linked hypertrophic cardiomyopathy caused by a novel mutation of the four-and-a-half LIM domain 1 gene. Circ Cardiovasc Genet. 2013;6:543–551. doi: 10.1161/CIRCGENETICS.113.000245.
18. Marian AJ. Challenges in the diagnosis of Anderson-Fabry disease: a deceptively simple and yet complicated genetic disease. J Am Coll Cardiol. 2016;68:1051–1053. doi: 10.1016/j.jacc.2016.06.026.
19. Gelb BD, Roberts AE, Tartaglia M. Cardiomyopathies in Noonan syndrome and the other RASopathies. Prog Pediatr Cardiol. 2015;39:13–19. doi: 10.1016/j.ppedcard.2015.01.002.
20. Elliott P, Baker R, Pasquale F, Quarta G, Ebrahim H, Mehta AB, Hughes DA; ACES study group. Prevalence of Anderson-Fabry disease in patients with hypertrophic cardiomyopathy: the European Anderson-Fabry disease survey. Heart. 2011;97:1957–1960. doi: 10.1136/heartjnl-2011-300364.
21. Pare JA, Fraser RG, Pirozynski WJ, Shanks JA, Stubington D. Hereditary cardiovascular dysplasia. A form of familial cardiomyopathy. Am J Med. 1961;31:37–62.
22. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62:999–1006.
23. Millat G, Bouvagnet P, Chevalier P, Dauphin C, Jouk PS, Da Costa A, Prieur F, Bresson JL, Faivre L, Eicher JC, Chassaing N, Crehalet H, Porcher R, Rodriguez-Lafrasse C, Rousson R. Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. Eur J Med Genet. 2010;53:261–267. doi: 10.1016/j.ejmg.2010.07.007.
24. Kaski JP, Syrris P, Esteban MT, Jenkins S, Pantazis A, Deanfield JE, McKenna WJ, Elliott PM. Prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy. Circ Cardiovasc Genet. 2009;2:436–441. doi: 10.1161/CIRCGENETICS.108.821314.
25. Erdmann J, Daehmlow S, Wischke S, Senyuva M, Werner U, Raible J, Tanis N, Dyachenko S, Hummel M, Hetzer R, Regitz-Zagrosek V. Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Clin Genet. 2003;64:339–349.
26. Richard P, Charron P, Carrier L, et al; EUROGENE Heart Failure Project. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003;107:2227–2232. doi: 10.1161/01.CIR.0000066323. 15244.54.
27. Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994;77:701–712.
28. Kimura A, Harada H, Park JE, et al. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet. 1997;16:379–382. doi: 10.1038/ng0897-379.
29. Mogensen J, Klausen IC, Pedersen AK, Egeblad H, Bross P, Kruse TA, Gregersen N, Hansen PS, Baandrup U, Borglum AD. Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. J Clin Invest. 1999;103:R39–R43. doi: 10.1172/JCI6460.
30. Poetter K, Jiang H, Hassanzadeh S, Master SR, Chang A, Dalakas MC, Rayment I, Sellers JR, Fananapazir L, Epstein ND. Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nat Genet. 1996;13:63–69. doi: 10.1038/ng0596-63.
31. Geier C, Gehmlich K, Ehler E, et al. Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy. Hum Mol Genet. 2008;17:2753–2765. doi: 10.1093/hmg/ddn160.
32. Walsh R, Buchan R, Wilk A, John S, Felkin LE, Thomson KL, Chiaw TH, Loong CC, Pua CJ, Raphael C, Prasad S, Barton PJ, Funke B, Watkins H, Ware JS, Cook SA. Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes [published online ahead of print January 11, 2017]. Eur Heart J. doi: 10.1093/eurheartj/ehw603.
33. Walsh R, Thomson KL, Ware JS, et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017;19:192–203. doi: 10.1038/gim.2016.90.
34. Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A. Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem Biophys Res Commun. 1999;262:411–417. doi: 10.1006/bbrc.1999.1221.
35. Hayashi T, Arimura T, Itoh-Satoh M, et al. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol. 2004;44:2192–2201. doi: 10.1016/j.jacc.2004.08.058.
36. Marian AJ. Hypertrophic cardiomyopathy: from genetics to treatment. Eur J Clin Invest. 2010;40:360–369.
37. Kimura A. Molecular genetics and pathogenesis of cardiomyopathy. J Hum Genet. 2016;61:41–50. doi: 10.1038/jhg.2015.83.
38. Ho CY, Charron P, Richard P, Girolami F, Van Spaendonck-Zwarts KY, Pinto Y. Genetic advances in sarcomeric cardiomyopathies: state of the art. Cardiovasc Res. 2015;105:397–408. doi: 10.1093/cvr/cvv025.
39. Osio A, Tan L, Chen SN, Lombardi R, Nagueh SF, Shete S, Roberts R, Willerson JT, Marian AJ. Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy. Circ Res. 2007;100:766–768. doi: 10.1161/01. RES.0000263008.66799.aa.
40. Chen SN, Czernuszewicz G, Tan Y, Lombardi R, Jin J, Willerson JT, Marian AJ. Human molecular genetic and functional studies identify TRIM63, encoding Muscle RING Finger Protein 1, as a novel gene for human hypertrophic cardiomyopathy. Circ Res. 2012;111:907–919. doi: 10.1161/CIRCRESAHA.112.270207.
41. Friedrich FW, Wilding BR, Reischmann S, et al. Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy. Hum Mol Genet. 2012;21:3237–3254. doi: 10.1093/hmg/dds157.
42. Landstrom AP, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester DJ, Ommen SR, Potter JD, Ackerman MJ. Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. J Mol Cell Cardiol. 2008;45:281–288. doi: 10.1016/j.yjmcc.2008.05.003.
43. Carniel E, Taylor MR, Sinagra G, et al. Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy. Circulation. 2005;112:54–59. doi: 10.1161/CIRCULATIONAHA.104.507699.
44. Landstrom AP, Adekola BA, Bos JM, Ommen SR, Ackerman MJ. PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing. Am Heart J. 2011;161:165–171. doi: 10.1016/j.ahj.2010. 08.001.
45. Hayashi T, Arimura T, Ueda K, Shibata H, Hohda S, Takahashi M, Hori H, Koga Y, Oka N, Imaizumi T, Yasunami M, Kimura A. Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy. Biochem Biophys Res Commun. 2004;313:178–184.
46. Almomani R, Verhagen JM, Herkert JC, et al. Biallelic truncating mutations in ALPK3 cause severe pediatric cardiomyopathy. J Am Coll Cardiol. 2016;67:515–525. doi: 10.1016/j.jacc.2015.10.093.
47. Landstrom AP, Weisleder N, Batalden KB, Bos JM, Tester DJ, Ommen SR, Wehrens XH, Claycomb WC, Ko JK, Hwang M, Pan Z, Ma J, Ackerman MJ. Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans. J Mol Cell Cardiol. 2007;42:1026–1035. doi: 10.1016/j.yjmcc.2007.04.006.
48. Marian AJ. Nature's genetic gradients and the clinical phenotype. Circ Cardiovasc Genet. 2009;2:537–539. doi: 10.1161/CIRCGENETICS. 109.921940.
49. Marian AJ. Causality in genetics: the gradient of genetic effects and back to Koch's postulates of causality. Circ Res. 2014;114:e18–e21. doi: 10.1161/CIRCRESAHA.114.302904.
50. Marian AJ. The case of “missing causal genes” and the practice of medicine: a Sherlock Holmes approach of deductive reasoning. Circ Res. 2016;119:21–24. doi: 10.1161/CIRCRESAHA.116.308830.
51. MacArthur DG, Manolio TA, Dimmock DP, et al. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014;508:469–476. doi: 10.1038/nature13127.
52. Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR; 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526:68–74. doi: 10.1038/nature15393.
53. Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA; 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061–1073. doi: 10.1038/nature09534.
54. Saltzman AJ, Mancini-DiNardo D, Li C, et al. Short communication: the cardiac myosin binding protein C Arg502Trp mutation: a common cause of hypertrophic cardiomyopathy. Circ Res. 2010;106:1549–1552. doi: 10.1161/CIRCRESAHA.109.216291.
55. Page SP, Kounas S, Syrris P, Christiansen M, Frank-Hansen R, Andersen PS, Elliott PM, McKenna WJ. Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome. Circ Cardiovasc Genet. 2012;5:156–166. doi: 10.1161/CIRCGENETICS.111.960831.
56. Alfares AA, Kelly MA, McDermott G, et al. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015;17:880–888. doi: 10.1038/gim.2014.205.
57. Hodatsu A, Konno T, Hayashi K, Funada A, Fujita T, Nagata Y, Fujino N, Kawashiri MA, Yamagishi M. Compound heterozygosity deteriorates phenotypes of hypertrophic cardiomyopathy with founder MYBPC3 mutation: evidence from patients and zebrafish models. Am J Physiol Heart Circ Physiol. 2014;307:H1594–H1604. doi: 10.1152/ajpheart. 00637.2013.
58. Dausse E, Komajda M, Fetler L, Dubourg O, Dufour C, Carrier L, Wisnewsky C, Bercovici J, Hengstenberg C, al-Mahdawi S. Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and identification of a hot spot for mutations in the beta-myosin heavy chain gene. J Clin Invest. 1993;92:2807–2813. doi: 10.1172/JCI116900.
59. Forissier JF, Carrier L, Farza H, et al. Codon 102 of the cardiac troponin T gene is a putative hot spot for mutations in familial hypertrophic cardiomyopathy. Circulation. 1996;94:3069–3073.
60. Coviello DA, Maron BJ, Spirito P, Watkins H, Vosberg HP, Thierfelder L, Schoen FJ, Seidman JG, Seidman CE. Clinical features of hypertrophic cardiomyopathy caused by mutation of a “hot spot” in the alpha-tropomyosin gene. J Am Coll Cardiol. 1997;29:635–640.
61. Marian AJ, Yu QT, Mares A, Jr, Hill R, Roberts R, Perryman MB. Detection of a new mutation in the beta-myosin heavy chain gene in an individual with hypertrophic cardiomyopathy. J Clin Invest. 1992;90:2156–2165. doi: 10.1172/JCI116101.
62. Watkins H, Seidman CE, Seidman JG, Feng HS, Sweeney HL. Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy. Evidence for a dominant negative action. J Clin Invest. 1996;98:2456–2461. doi: 10.1172/JCI119063.
63. Blair E, Redwood C, de Jesus Oliveira M, Moolman-Smook JC, Brink P, Corfield VA, Ostman-Smith I, Watkins H. Mutations of the light mero-myosin domain of the beta-myosin heavy chain rod in hypertrophic cardiomyopathy. Circ Res. 2002;90:263–269.
64. Homburger JR, Green EM, Caleshu C, Sunitha MS, Taylor RE, Ruppel KM, Metpally RP, Colan SD, Michels M, Day SM, Olivotto I, Bustamante CD, Dewey FE, Ho CY, Spudich JA, Ashley EA. Multidimensional structure-function relationships in human beta-cardiac myosin from population-scale genetic variation. Proc Natl Acad Sci USA. 2016;113:6701–6706. doi: 10.1073/pnas.1606950113.
65. Towe EC, Bos JM, Ommen SR, Gersh BJ, Ackerman MJ. Genotype-phenotype correlations in apical variant hypertrophic cardiomyopathy. Congenit Heart Dis. 2015;10:E139–E145. doi: 10.1111/chd.12242.
66. Chapman KB, Solomon SD, Boeke JD. SDH1, the gene encoding the suc-cinate dehydrogenase flavoprotein subunit from Saccharomyces cerevi-siae. Gene. 1992;118:131–136.
67. Marian AJ, Belmont J. Strategic approaches to unraveling genetic causes of cardiovascular diseases. Circ Res. 2011;108:1252–1269. doi: 10.1161/CIRCRESAHA.110.236067.
68. Blair E, Price SJ, Baty CJ, Ostman-Smith I, Watkins H. Mutations in cis can confound genotype-phenotype correlations in hypertrophic cardiomyopathy. J Med Genet. 2001;38:385–388.
69. Maron BJ, Maron MS, Semsarian C. Double or compound sarcomere mutations in hypertrophic cardiomyopathy: a potential link to sudden death in the absence of conventional risk factors. Heart Rhythm. 2012;9:57–63. doi: 10.1016/j.hrthm.2011.08.009.
70. Girolami F, Ho CY, Semsarian C, Baldi M, Will ML, Baldini K, Torricelli F, Yeates L, Cecchi F, Ackerman MJ, Olivotto I. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. J Am Coll Cardiol. 2010;55:1444–1453. doi: 10.1016/j.jacc.2009.11.062.
71. Lekanne Deprez RH, Muurling-Vlietman JJ, Hruda J, Baars MJ, Wijnaendts LC, Stolte-Dijkstra I, Alders M, van Hagen JM. Two cases of severe neonatal hypertrophic cardiomyopathy caused by compound heterozygous mutations in the MYBPC3 gene. J Med Genet. 2006;43:829–832. doi: 10.1136/jmg.2005.040329.
72. Van Driest SL, Vasile VC, Ommen SR, Will ML, Tajik AJ, Gersh BJ, Ackerman MJ. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004;44:1903–1910. doi: 10.1016/j.jacc.2004.07.045.
73. Li L, Bainbridge MN, Tan Y, Willerson JT, Marian AJ. A potential oligogenic etiology of hypertrophic cardiomyopathy: a classic single-gene disorder. Circ Res. 2017;120:1084–1090. doi: 10.1161/CIRCRESAHA.116.310559.
74. Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. J Med Genet. 2005;42:e59. doi: 10.1136/jmg.2005.033886.
75. van Dijk SJ, Dooijes D, dos Remedios C, Michels M, Lamers JM, Winegrad S, Schlossarek S, Carrier L, ten Cate FJ, Stienen GJ, van der Velden J. Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy: haploinsufficiency, deranged phosphorylation, and car-diomyocyte dysfunction. Circulation. 2009;119:1473–1483. doi: 10.1161/CIRCULATIONAHA.108.838672.
76. Popp MW, Maquat LE. Leveraging rules of nonsense-mediated mRNA decay for genome engineering and personalized medicine. Cell. 2016;165:1319–1322. doi: 10.1016/j.cell.2016.05.053.
77. Siwaszek A, Ukleja M, Dziembowski A. Proteins involved in the degradation of cytoplasmic mRNA in the major eukaryotic model systems. RNA Biol. 2014;11:1122–1136. doi: 10.4161/rna.34406.
78. Vasudevan S, Peltz SW, Wilusz CJ. Non-stop decay–a new mRNA surveillance pathway. Bioessays. 2002;24:785–788. doi: 10.1002/bies.10153.
79. Frischmeyer PA, van Hoof A, O'Donnell K, Guerrerio AL, Parker R, Dietz HC. An mRNA surveillance mechanism that eliminates transcripts lacking termination codons. Science. 2002;295:2258–2261. doi: 10.1126/science.1067338.
80. Carrier L, Bonne G, Bährend E, et al. Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy. Circ Res. 1997;80:427–434.
81. Schlossarek S, Mearini G, Carrier L. Cardiac myosin-binding protein C in hypertrophic cardiomyopathy: mechanisms and therapeutic opportunities. J Mol Cell Cardiol. 2011;50:613–620. doi: 10.1016/j.yjmcc.2011.01.014.
82. Marston S, Copeland O, Jacques A, Livesey K, Tsang V, McKenna WJ, Jalilzadeh S, Carballo S, Redwood C, Watkins H. Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. Circ Res. 2009;105:219–222. doi: 10.1161/CIRCRESAHA.109.202440.
83. Rottbauer W, Gautel M, Zehelein J, Labeit S, Franz WM, Fischer C, Vollrath B, Mall G, Dietz R, Kübler W, Katus HA. Novel splice donor site mutation in the cardiac myosin-binding protein-C gene in familial hypertrophic cardiomyopathy. Characterization of cardiac transcript and protein. J Clin Invest. 1997;100:475–482. doi: 10.1172/JCI119555.
84. Marston S, Copeland O, Gehmlich K, Schlossarek S, Carrier L, Carrrier L. How do MYBPC3 mutations cause hypertrophic cardiomyopathy? JMuscleResCellMotil.2012;33:75–80.doi:10.1007/s10974-011-9268-3.
85. Moolman JA, Reith S, Uhl K, Bailey S, Gautel M, Jeschke B, Fischer C, Ochs J, McKenna WJ, Klues H, Vosberg HP. A newly created splice donor site in exon 25 of the MyBP-C gene is responsible for inherited hypertrophic cardiomyopathy with incomplete disease penetrance. Circulation. 2000;101:1396–1402.
86. Sarikas A, Carrier L, Schenke C, Doll D, Flavigny J, Lindenberg KS, Eschenhagen T, Zolk O. Impairment of the ubiquitin-proteasome system by truncated cardiac myosin binding protein C mutants. Cardiovasc Res. 2005;66:33–44. doi: 10.1016/j.cardiores.2005.01.004.
87. Barefield D, Kumar M, Gorham J, Seidman JG, Seidman CE, de Tombe PP, Sadayappan S. Haploinsufficiency of MYBPC3 exacerbates the development of hypertrophic cardiomyopathy in heterozygous mice. J Mol Cell Cardiol. 2015;79:234–243. doi: 10.1016/j.yjmcc.2014.11.018.
88. Tripathi S, Schultz I, Becker E, Montag J, Borchert B, Francino A, Navarro-Lopez F, Perrot A, Özcelik C, Osterziel KJ, McKenna WJ, Brenner B, Kraft T. Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy. Basic Res Cardiol. 2011;106:1041–1055. doi: 10.1007/s00395-011-0205-9.
89. Kraft T, Montag J, Radocaj A, Brenner B. Hypertrophic cardiomyopathy: cell-to-cell imbalance in gene expression and contraction force as trigger for disease phenotype development. Circ Res. 2016;119:992–995. doi: 10.1161/CIRCRESAHA.116.309804.
90. Helms AS, Davis FM, Coleman D, Bartolone SN, Glazier AA, Pagani F, Yob JM, Sadayappan S, Pedersen E, Lyons R, Westfall MV, Jones R, Russell MW, Day SM. Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy. Circ Cardiovasc Genet. 2014;7:434–443. doi: 10.1161/CIRCGENETICS.113.000448.
91. Wolny M, Colegrave M, Colman L, White E, Knight PJ, Peckham M. Cardiomyopathy mutations in the tail of β-cardiac myosin modify the coiled-coil structure and affect integration into thick filaments in muscle sarcomeres in adult cardiomyocytes. J Biol Chem. 2013;288:31952–31962. doi: 10.1074/jbc.M113.513291.
92. Geisterfer-Lowrance AA, Christe M, Conner DA, Ingwall JS, Schoen FJ, Seidman CE, Seidman JG. A mouse model of familial hypertrophic cardiomyopathy. Science. 1996;272:731–734.
93. Tardiff JC, Factor SM, Tompkins BD, Hewett TE, Palmer BM, Moore RL, Schwartz S, Robbins J, Leinwand LA. A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy. J Clin Invest. 1998;101:2800–2811. doi: 10.1172/JCI2389.
94. Frey N, Brixius K, Schwinger RH, Benis T, Karpowski A, Lorenzen HP, Luedde M, Katus HA, Franz WM. Alterations of tension-dependent ATP utilization in a transgenic rat model of hypertrophic cardiomyopathy. J Biol Chem. 2006;281:29575–29582. doi: 10.1074/jbc.M507740200.
95. Oberst L, Zhao G, Park JT, Brugada R, Michael LH, Entman ML, Roberts R, Marian AJ. Dominant-negative effect of a mutant cardiac troponin T on cardiac structure and function in transgenic mice. J Clin Invest. 1998;102:1498–1505. doi: 10.1172/JCI4088.
96. Marian AJ, Wu Y, Lim DS, McCluggage M, Youker K, Yu QT, Brugada R, DeMayo F, Quinones M, Roberts R. A transgenic rabbit model for human hypertrophic cardiomyopathy. J Clin Invest. 1999;104:1683–1692. doi: 10.1172/JCI7956.
97. Lim DS, Oberst L, McCluggage M, Youker K, Lacy J, DeMayo F, Entman ML, Roberts R, Michael LH, Marian AJ. Decreased left ventricular ejection fraction in transgenic mice expressing mutant cardiac troponin T-Q(92), responsible for human hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2000;32:365–374. doi: 10.1006/jmcc.1999.1081.
98. Fraysse B, Weinberger F, Bardswell SC, Cuello F, Vignier N, Geertz B, Starbatty J, Krämer E, Coirault C, Eschenhagen T, Kentish JC, Avkiran M, Carrier L. Increased myofilament Ca2+ sensitivity and diastolic dysfunction as early consequences of Mybpc3 mutation in heterozygous knock-in mice. J Mol Cell Cardiol. 2012;52:1299–1307. doi: 10.1016/j.yjmcc.2012.03.009.
99. Debold EP, Schmitt JP, Patlak JB, Beck SE, Moore JR, Seidman JG, Seidman C, Warshaw DM. Hypertrophic and dilated cardiomyopathy mutations differentially affect the molecular force generation of mouse alpha-cardiac myosin in the laser trap assay. Am J Physiol Heart Circ Physiol. 2007;293:H284–H291. doi: 10.1152/ajpheart.00128.2007.
100. Lompré AM, Nadal-Ginard B, Mahdavi V. Expression of the cardiac ventricular alpha- and beta-myosin heavy chain genes is developmentally and hormonally regulated. J Biol Chem. 1984;259:6437–6446.
101. Miyata S, Minobe W, Bristow MR, Leinwand LA. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res. 2000;86:386–390.
102. Reiser PJ, Portman MA, Ning XH, Schomisch Moravec C. Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. Am J Physiol Heart Circ Physiol. 2001;280:H1814–H1820.
103. Walklate J, Ujfalusi Z, Geeves MA. Myosin isoforms and the mecha-nochemical cross-bridge cycle. J Exp Biol. 2016;219:168–174. doi: 10.1242/jeb.124594.
104. Schwartz K, Lecarpentier Y, Martin JL, Lompré AM, Mercadier JJ, Swynghedauw B. Myosin isoenzymic distribution correlates with speed of myocardial contraction. J Mol Cell Cardiol. 1981;13:1071–1075.
105. Litten RZ 3rd, Martin BJ, Low RB, Alpert NR. Altered myosin isozyme patterns from pressure-overloaded and thyrotoxic hypertrophied rabbit hearts. Circ Res. 1982;50:856–864.
106. Witjas-Paalberends ER, Piroddi N, Stam K, et al. Mutations in MYH7 reduce the force generating capacity of sarcomeres in human familial hypertrophic cardiomyopathy. Cardiovasc Res. 2013;99:432–441. doi: 10.1093/cvr/cvt119.
107. Witjas-Paalberends ER, Güçlü A, Germans T, et al. Gene-specific increase in the energetic cost of contraction in hypertrophic cardiomyopathy caused by thick filament mutations. Cardiovasc Res. 2014;103:248–257. doi: 10.1093/cvr/cvu127.
108. Bloemink M, Deacon J, Langer S, Vera C, Combs A, Leinwand L, Geeves MA. The hypertrophic cardiomyopathy myosin mutation R453C alters ATP binding and hydrolysis of human cardiac β-myosin. J Biol Chem. 2014;289:5158–5167. doi: 10.1074/jbc.M113.511204.
109. Nagueh SF, Chen S, Patel R, Tsybouleva N, Lutucuta S, Kopelen HA, Zoghbi WA, Quiñones MA, Roberts R, Marian AJ. Evolution of expression of cardiac phenotypes over a 4-year period in the beta-myosin heavy chain-Q403 transgenic rabbit model of human hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2004;36:663–673. doi: 10.1016/j.yjmcc.2004.02.010.
110. Lombardi R, Bell A, Senthil V, Sidhu J, Noseda M, Roberts R, Marian AJ. Differential interactions of thin filament proteins in two cardiac troponin T mouse models of hypertrophic and dilated cardiomyopathies. Cardiovasc Res. 2008;79:109–117. doi: 10.1093/cvr/cvn078.
111. Solaro RJ, Varghese J, Marian AJ, Chandra M. Molecular mechanisms of cardiac myofilament activation: modulation by pH and a troponin T mutant R92Q. Basic Res Cardiol. 2002;97(suppl 1):I102–I110.
112. Crilley JG, Boehm EA, Blair E, Rajagopalan B, Blamire AM, Styles P, McKenna WJ, Ostman-Smith I, Clarke K, Watkins H. Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J Am Coll Cardiol. 2003;41:1776–1782.
113. Hoskins AC, Jacques A, Bardswell SC, McKenna WJ, Tsang V, dos Remedios CG, Ehler E, Adams K, Jalilzadeh S, Avkiran M, Watkins H, Redwood C, Marston SB, Kentish JC. Normal passive viscoelasticity but abnormal myofibrillar force generation in human hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2010;49:737–745. doi: 10.1016/j.yjmcc.2010.06.006.
114. Gupte TM, Haque F, Gangadharan B, Sunitha MS, Mukherjee S, Anandhan S, Rani DS, Mukundan N, Jambekar A, Thangaraj K, Sowdhamini R, Sommese RF, Nag S, Spudich JA, Mercer JA. Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies. J Biol Chem. 2015;290:7003–7015. doi: 10.1074/jbc.M114.596676.
115. Cordero-Reyes AM, Youker K, Hamilton DJ, Torre-Amione G, Marian AJ, Nagueh SF. Molecular, cellular, and functional characterization of myocardial regions in hypertrophic cardiomyopathy. Circ Cardiovasc Imaging. 2012;5:419–422. doi: 10.1161/CIRCIMAGING.112.972802.
116. Kraft T, Witjas-Paalberends ER, Boontje NM, Tripathi S, Brandis A, Montag J, Hodgkinson JL, Francino A, Navarro-Lopez F, Brenner B, Stienen GJ, van der Velden J. Familial hypertrophic cardiomyopathy: functional effects of myosin mutation R723G in cardiomyocytes. J Mol Cell Cardiol. 2013;57:13–22. doi: 10.1016/j.yjmcc.2013.01.001.
117. Sequeira V, Wijnker PJ, Nijenkamp LL, et al. Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations. Circ Res. 2013;112:1491–1505. doi: 10.1161/CIRCRESAHA.111.300436.
118. Li RK, Li G, Mickle DA, Weisel RD, Merante F, Luss H, Rao V, Christakis GT, Williams WG. Overexpression of transforming growth factor-beta1 and insulin-like growth factor-I in patients with idiopathic hypertrophic cardiomyopathy. Circulation. 1997;96:874–881.
119. Helms AS, Alvarado FJ, Yob J, Tang VT, Pagani F, Russell MW, Valdivia HH, Day SM. Genotype-dependent and -independent calcium signaling dysregulation in human hypertrophic cardiomyopathy. Circulation. 2016;134:1738–1748. doi: 10.1161/CIRCULATIONAHA.115.020086.
120. Ruggiero A, Chen SN, Lombardi R, Rodriguez G, Marian AJ. Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity. Cardiovasc Res. 2013;97:44–54. doi: 10.1093/cvr/cvs294.
121. Fatkin D, McConnell BK, Mudd JO, Semsarian C, Moskowitz IG, Schoen FJ, Giewat M, Seidman CE, Seidman JG. An abnormal Ca(2+) response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy. J Clin Invest. 2000;106:1351–1359. doi: 10.1172/JCI11093.
122. Teekakirikul P, Eminaga S, Toka O, et al. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β. J Clin Invest. 2010;120:3520–3529. doi: 10.1172/JCI42028.
123. Senthil V, Chen SN, Tsybouleva N, Halder T, Nagueh SF, Willerson JT, Roberts R, Marian AJ. Prevention of cardiac hypertrophy by atorvastatin in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circ Res. 2005;97:285–292. doi: 10.1161/01.RES.0000177090.07296. ac.
124. Patel R, Nagueh SF, Tsybouleva N, Abdellatif M, Lutucuta S, Kopelen HA, Quinones MA, Zoghbi WA, Entman ML, Roberts R, Marian AJ. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation. 2001;104:317–324.
125. Kuster DW, Mulders J, Ten Cate FJ, Michels M, Dos Remedios CG, da Costa Martins PA, van der Velden J, Oudejans CB. MicroRNA transcrip-tome profiling in cardiac tissue of hypertrophic cardiomyopathy patients with MYBPC3 mutations. J Mol Cell Cardiol. 2013;65:59–66. doi: 10.1016/j.yjmcc.2013.09.012.
126. Leptidis S, El Azzouzi H, Lok SI, de Weger R, Olieslagers S, Olieslagers S, Kisters N, Silva GJ, Heymans S, Cuppen E, Berezikov E, De Windt LJ, da Costa Martins P. A deep sequencing approach to uncover the miR-NOME in the human heart. PLoS One. 2013;8:e57800. doi: 10.1371/journal.pone.0057800.
127. Yang W, Li Y, He F, Wu H. Microarray profiling of long non-coding RNA (lncRNA) associated with hypertrophic cardiomyopathy. BMC Cardiovasc Disord. 2015;15:62. doi: 10.1186/s12872-015-0056-7.
128. Christodoulou DC, Wakimoto H, Onoue K, et al. 5'RNA-Seq identifies Fhl1 as a genetic modifier in cardiomyopathy. J Clin Invest. 2014;124:1364–1370. doi: 10.1172/JCI70108.
129. Sasagawa S, Nishimura Y, Okabe S, Murakami S, Ashikawa Y, Yuge M, Kawaguchi K, Kawase R, Okamoto R, Ito M, Tanaka T. Downregulation of GSTK1 is a common mechanism underlying hypertrophic cardiomyopathy. Front Pharmacol. 2016;7:162. doi: 10.3389/fphar.2016.00162.
130. Marian AJ. Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy. Lancet. 2000;355:58–60.
131. Lan F, Lee AS, Liang P, et al. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell. 2013;12:101–113. doi: 10.1016/j.stem.2012.10.010.
132. Watkins H, McKenna WJ, Thierfelder L, Suk HJ, Anan R, O'Donoghue A, Spirito P, Matsumori A, Moravec CS, Seidman JG. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med. 1995;332:1058–1064. doi: 10.1056/NEJM199504203321603.
133. Watkins H, Rosenzweig A, Hwang DS, Levi T, McKenna W, Seidman CE, Seidman JG. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med. 1992;326:1108–1114. doi: 10.1056/NEJM199204233261703.
134. Marian AJ, Mares A, Jr, Kelly DP, Yu QT, Abchee AB, Hill R, Roberts R. Sudden cardiac death in hypertrophic cardiomyopathy. Variability in phenotypic expression of beta-myosin heavy chain mutations. Eur Heart J. 1995;16:368–376.
135. Lopes LR, Rahman MS, Elliott PM. A systematic review and meta-analysis of genotype-phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations. Heart. 2013;99:1800–1811. doi: 10.1136/heartjnl-2013-303939.
136. Marian AJ. On genetic and phenotypic variability of hypertrophic cardiomyopathy: nature versus nurture. J Am Coll Cardiol. 2001;38:331–334.
137. Coppini R, Ho CY, Ashley E, Day S, Ferrantini C, Girolami F, Tomberli B, Bardi S, Torricelli F, Cecchi F, Mugelli A, Poggesi C, Tardiff J, Olivotto I. Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. J Am Coll Cardiol. 2014;64:2589–2600. doi: 10.1016/j.jacc.2014.09.059.
138. Daw EW, Chen SN, Czernuszewicz G, Lombardi R, Lu Y, Ma J, Roberts R, Shete S, Marian AJ. Genome-wide mapping of modifier chromosomal loci for human hypertrophic cardiomyopathy. Hum Mol Genet. 2007;16:2463–2471. doi: 10.1093/hmg/ddm202.
139. Tiret L, Rigat B, Visvikis S, Breda C, Corvol P, Cambien F, Soubrier F. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet. 1992;51:197–205.
140. Lechin M, Quiñones MA, Omran A, Hill R, Yu QT, Rakowski H, Wigle D, Liew CC, Sole M, Roberts R. Angiotensin-I converting enzyme genotypes and left ventricular hypertrophy in patients with hypertrophic cardiomyopathy. Circulation. 1995;92:1808–1812.
141. Marian AJ, Yu QT, Workman R, Greve G, Roberts R. Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lancet. 1993;342:1085–1086.
142. Kaufman BD, Auerbach S, Reddy S, Manlhiot C, Deng L, Prakash A, Printz BF, Gruber D, Papavassiliou DP, Hsu DT, Sehnert AJ, Chung WK, Mital S. RAAS gene polymorphisms influence progression of pediatric hypertrophic cardiomyopathy. Hum Genet. 2007;122:515–523. doi: 10.1007/s00439-007-0429-9.
143. Mouton JM, van der Merwe L, Goosen A, Revera M, Brink PA, Moolman-Smook JC, Kinnear C. MYBPH acts as modifier of cardiac hypertrophy in hypertrophic cardiomyopathy (HCM) patients. Hum Genet. 2016;135:477–483. doi: 10.1007/s00439-016-1649-7.
144. Brugada R, Kelsey W, Lechin M, Zhao G, Yu QT, Zoghbi W, Quinones M, Elstein E, Omran A, Rakowski H, Wigle D, Liew CC, Sole M, Roberts R, Marian AJ. Role of candidate modifier genes on the phenotypic expression of hypertrophy in patients with hypertrophic cardiomyopathy. J Investig Med. 1997;45:542–551.
145. Fujino N, Shimizu M, Ino H, Yamaguchi M, Yasuda T, Nagata M, Konno T, Mabuchi H. A novel mutation Lys273Glu in the cardiac troponin T gene shows high degree of penetrance and transition from hypertrophic to dilated cardiomyopathy. Am J Cardiol. 2002;89:29–33.
146. Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, Gimeno JR, Elliott P, McKenna WJ. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest. 2003;111:209–216. doi: 10.1172/JCI16336.
147. Hoedemaekers YM, Caliskan K, Majoor-Krakauer D, van de Laar I, Michels M, Witsenburg M, ten Cate FJ, Simoons ML, Dooijes D. Cardiac beta-myosin heavy chain defects in two families with non-compaction cardiomyopathy: linking non-compaction to hypertrophic, restrictive, and dilated cardiomyopathies. Eur Heart J. 2007;28:2732–2737. doi: 10.1093/eurheartj/ehm429.
148. Dellefave LM, Pytel P, Mewborn S, Mora B, Guris DL, Fedson S, Waggoner D, Moskowitz I, McNally EM. Sarcomere mutations in cardiomyopathy with left ventricular hypertrabeculation. Circ Cardiovasc Genet. 2009;2:442–449. doi: 10.1161/CIRCGENETICS.109.861955.
149. Kamisago M, Sharma SD, DePalma SR, Solomon S, Sharma P, McDonough B, Smoot L, Mullen MP, Woolf PK, Wigle ED, Seidman JG, Seidman CE. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. New Eng J Med. 2000;343:1688–1696.
150. Sommese RF, Nag S, Sutton S, Miller SM, Spudich JA, Ruppel KM. Effects of troponin T cardiomyopathy mutations on the calcium sensitivity of the regulated thin filament and the actomyosin cross-bridge kinetics of human β-cardiac myosin. PLoS One. 2013;8:e83403. doi: 10.1371/journal.pone.0083403.
151. Hershberger RE, Pinto JR, Parks SB, Kushner JD, Li D, Ludwigsen S, Cowan J, Morales A, Parvatiyar MS, Potter JD. Clinical and functional characterization of TNNT2 mutations identified in patients with dilated cardiomyopathy. Circ Cardiovasc Genet. 2009;2:306–313. doi: 10.1161/CIRCGENETICS.108.846733.
152. Jagatheesan G, Rajan S, Schulz EM, Ahmed RP, Petrashevskaya N, Schwartz A, Boivin GP, Arteaga GM, Wang T, Wang YG, Ashraf M, Liggett SB, Lorenz J, Solaro RJ, Wieczorek DF. An internal domain of beta-tropomyosin increases myofilament Ca(2+) sensitivity. Am J Physiol Heart Circ Physiol. 2009;297:H181–H190. doi: 10.1152/ajpheart.00329.2008.
153. Harada K, Potter JD. Familial hypertrophic cardiomyopathy mutations from different functional regions of troponin T result in different effects on the pH and Ca2+ sensitivity of cardiac muscle contraction. J Biol Chem. 2004;279:14488–14495. doi: 10.1074/jbc.M309355200.
154. Revera M, van der Merwe L, Heradien M, Goosen A, Corfield VA, Brink PA, Moolman-Smook JC. Troponin T and beta-myosin mutations have distinct cardiac functional effects in hypertrophic cardiomyopathy patients without hypertrophy. Cardiovasc Res. 2008;77:687–694. doi: 10.1093/cvr/cvm075.
155. Moore JR, Leinwand L, Warshaw DM. Understanding cardiomyopathy phenotypes based on the functional impact of mutations in the myosin motor. Circ Res. 2012;111:375–385. doi: 10.1161/CIRCRESAHA. 110.223842.
156. Davis J, Davis LC, Correll RN, et al. A tension-based model distinguishes hypertrophic versus dilated cardiomyopathy. Cell. 2016;165:1147–1159. doi: 10.1016/j.cell.2016.04.002.
157. Jan MF, Tajik AJ. Modern imaging techniques in cardiomyopathies. Circ Res. 2017;121:874–891. doi: 10.1161/CIRCRESAHA.117.309600.
158. Braunwald E, Lambrew CT, Rockoff SD, Ross J, Jr, Morrow AG. Idiopathic hypertrophic subaortic stenosis. I. A description of the disease based upon an analysis of 64 patients. Circulation. 1964;30(suppl 4):3–119.
159. Henry WL, Clark CE, Epstein SE. Asymmetric septal hypertrophy. Echocardiographic identification of the pathognomonic anatomic abnormality of IHSS. Circulation. 1973;47:225–233.
160. Maron MS, Olivotto I, Harrigan C, Appelbaum E, Gibson CM, Lesser JR, Haas TS, Udelson JE, Manning WJ, Maron BJ. Mitral valve abnormalities identified by cardiovascular magnetic resonance represent a primary phenotypic expression of hypertrophic cardiomyopathy. Circulation. 2011;124:40–47. doi: 10.1161/CIRCULATIONAHA. 110.985812.
161. Malik R, Maron MS, Rastegar H, Pandian NG. Hypertrophic cardiomyopathy with right ventricular outflow tract and left ventricular intracavi-tary obstruction. Echocardiography. 2014;31:682–685. doi: 10.1111/echo.12543.
162. Teare D. Asymmetrical hypertrophy of the heart in young adults. Br Heart J. 1958;20:1–8.
163. Davies MJ, McKenna WJ. Hypertrophic cardiomyopathy–pathology and pathogenesis. Histopathology. 1995;26:493–500.
164. Davies MJ. The current status of myocardial disarray in hypertrophic cardiomyopathy. Br Heart J. 1984;51:361–363.
165. Varnava AM, Elliott PM, Baboonian C, Davison F, Davies MJ, McKenna WJ. Hypertrophic cardiomyopathy: histopathological features of sudden death in cardiac troponin T disease. Circulation. 2001;104:1380–1384.
166. McGill LA, Ismail TF, Nielles-Vallespin S, et al. Reproducibility of in-vivo diffusion tensor cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Cardiovasc Magn Reson. 2012;14:86. doi: 10.1186/1532-429X-14-86.
167. Almaas VM, Haugaa KH, Strøm EH, Scott H, Dahl CP, Leren TP, Geiran OR, Endresen K, Edvardsen T, Aakhus S, Amlie JP. Increased amount of interstitial fibrosis predicts ventricular arrhythmias, and is associated with reduced myocardial septal function in patients with obstructive hypertrophic cardiomyopathy. Europace. 2013;15:1319–1327. doi: 10.1093/europace/eut028.
168. McLELLAN AJ, Ellims AH, Prabhu S, Voskoboinik A, Iles LM, Hare JL, Kaye DM, Macciocca I, Mariani JA, Kalman JM, Taylor AJ, Kistler PM. Diffuse ventricular fibrosis on cardiac magnetic resonance imaging associates with ventricular tachycardia in patients with hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol. 2016;27:571–580. doi: 10.1111/jce.12948.
169. Briasoulis A, Mallikethi-Reddy S, Palla M, Alesh I, Afonso L. Myocardial fibrosis on cardiac magnetic resonance and cardiac outcomes in hypertrophic cardiomyopathy: a meta-analysis. Heart. 2015;101:1406–1411. doi: 10.1136/heartjnl-2015-307682.
170. O'Hanlon R, Grasso A, Roughton M, et al. Prognostic significance of myocardial fibrosis in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2010;56:867–874. doi: 10.1016/j.jacc.2010.05.010.
171. Schelbert EB, Piehler KM, Zareba KM, Moon JC, Ugander M, Messroghli DR, Valeti US, Chang CC, Shroff SG, Diez J, Miller CA, Schmitt M, Kellman P, Butler J, Gheorghiade M, Wong TC. Myocardial fibrosis quantified by extracellular volume is associated with subsequent hospitalization for heart failure, death, or both across the spectrum of ejection fraction and heart failure stage. J Am Heart Assoc. 2015;4.
172. Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol. 1986;8:545–557.
173. Lombardi R, Betocchi S, Losi MA, Tocchetti CG, Aversa M, Miranda M, D'Alessandro G, Cacace A, Ciampi Q, Chiariello M. Myocardial collagen turnover in hypertrophic cardiomyopathy. Circulation. 2003;108:1455–1460. doi: 10.1161/01.CIR.0000090687.97972.10.
174. Ho CY, López B, Coelho-Filho OR, Lakdawala NK, Cirino AL, Jarolim P, Kwong R, González A, Colan SD, Seidman JG, Díez J, Seidman CE. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med. 2010;363:552–563. doi: 10.1056/NEJMoa1002659.
175. Ellims AH, Taylor AJ, Mariani JA, Ling LH, Iles LM, Maeder MT, Kaye DM. Evaluating the utility of circulating biomarkers of collagen synthesis in hypertrophic cardiomyopathy. Circ Heart Fail. 2014;7:271–278. doi: 10.1161/CIRCHEARTFAILURE.113.000665.
176. Kuusisto J, Kärjä V, Sipola P, Kholová I, Peuhkurinen K, Jääskeläinen P, Naukkarinen A, Ylä-Herttuala S, Punnonen K, Laakso M. Low-grade inflammation and the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy. Heart. 2012;98:1007–1013. doi: 10.1136/heartjnl-2011-300960.
177. Zen K, Irie H, Doue T, Takamiya M, Yamano T, Sawada T, Azuma A, Matsubara H. Analysis of circulating apoptosis mediators and proinflam-matory cytokines in patients with idiopathic hypertrophic cardiomyopathy: comparison between nonobstructive and dilated-phase hypertrophic cardiomyopathy. Int Heart J. 2005;46:231–244.
178. Moreno V, Hernández-Romero D, Vilchez JA, García-Honrubia A, Cambronero F, Casas T, González J, Martínez P, Climent V, de la Morena G, Valdés M, Marín F. Serum levels of high-sensitivity troponin T: a novel marker for cardiac remodeling in hypertrophic cardiomyopathy. J Card Fail. 2010;16:950–956. doi: 10.1016/j.cardfail.2010.07.245.
179. Fang L, Ellims AH, Moore XL, White DA, Taylor AJ, Chin-Dusting J, Dart AM. Circulating microRNAs as biomarkers for diffuse myocardial fibrosis in patients with hypertrophic cardiomyopathy. J Transl Med. 2015;13:314. doi: 10.1186/s12967-015-0672-0.
180. Derda AA, Thum S, Lorenzen JM, Bavendiek U, Heineke J, Keyser B, Stuhrmann M, Givens RC, Kennel PJ, Schulze PC, Widder JD, Bauersachs J, Thum T. Blood-based microRNA signatures differentiate various forms of cardiac hypertrophy. Int J Cardiol. 2015;196:115–122. doi: 10.1016/j.ijcard.2015.05.185.
181. Roncarati R, Viviani Anselmi C, Losi MA, et al. Circulating miR-29a, among other up-regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2014;63:920–927. doi: 10.1016/j.jacc.2013.09.041.
182. Brock R. Functional obstruction of the left ventricle; acquired aortic subvalvar stenosis. Guys Hosp Rep. 1957;106:221–238.
183. BROCK R. Functional obstruction of the left ventricle (acquired aortic subvalvar stenosis). Guys Hosp Rep. 1959;108:126–143.
184. Morrow AG, Braunwald E. Functional aortic stenosis; a malformation characterized by resistance to left ventricular outflow without anatomic obstruction. Circulation. 1959;20:181–189.
185. Maron MS, Olivotto I, Zenovich AG, Link MS, Pandian NG, Kuvin JT, Nistri S, Cecchi F, Udelson JE, Maron BJ. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006;114:2232–2239. doi: 10.1161/CIRCULATIONAHA.106.644682.
186. Shah JS, Esteban MT, Thaman R, Sharma R, Mist B, Pantazis A, Ward D, Kohli SK, Page SP, Demetrescu C, Sevdalis E, Keren A, Pellerin D, McKenna WJ, Elliott PM. Prevalence of exercise-induced left ventricular outflow tract obstruction in symptomatic patients with non-obstructive hypertrophic cardiomyopathy. Heart. 2008;94:1288–1294. doi: 10.1136/hrt.2007.126003.
187. Braunwald E, Oldham HN, Jr, Ross J, Jr, Linhart JW, Mason DT, Fort L 3rd. The circulatory response of patients with idiopathic hypertrophic subaortic stenosis to nitroglycerin and to the valsalva maneuver. Circulation. 1964;29:422–431.
188. Braunwald E, Ebert PA. Hemogynamic alterations in idiopathic hypertrophic subaortic stenosis induced by sympathomimetic drugs. Am J Cardiol. 1962;10:489–495.
189. Stewart S, Mason DT, Braunwald E. Impaired rate of left ventricular filling in idiopathic hypertrophic subaortic stenosis and valvular aortic stenosis. Circulation. 1968;37:8–14.
190. Guttmann OP, Pavlou M, O'Mahony C, Monserrat L, Anastasakis A, Rapezzi C, Biagini E, Gimeno JR, Limongelli G, Garcia-Pavia P, McKenna WJ, Omar RZ, Elliott PM; Hypertrophic Cardiomyopathy Outcomes Investigators. Prediction of thrombo-embolic risk in patients with hypertrophic cardiomyopathy (HCM Risk-CVA). Eur J Heart Fail. 2015;17:837–845. doi: 10.1002/ejhf.316.
191. Nagueh SF, McFalls J, Meyer D, Hill R, Zoghbi WA, Tam JW, Quiñones MA, Roberts R, Marian AJ. Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with sub-clinical disease. Circulation. 2003;108:395–398. doi: 10.1161/01. CIR.0000084500.72232.8D.
192. Kramer CM, Reichek N, Ferrari VA, Theobald T, Dawson J, Axel L. Regional heterogeneity of function in hypertrophic cardiomyopathy. Circulation. 1994;90:186–194.
193. Urbano-Moral JA, Rowin EJ, Maron MS, Crean A, Pandian NG. Investigation of global and regional myocardial mechanics with 3-dimensional speckle tracking echocardiography and relations to hypertrophy and fibrosis in hypertrophic cardiomyopathy. Circ Cardiovasc Imaging. 2014;7:11–19. doi: 10.1161/CIRCIMAGING. 113.000842.
194. Sen-Chowdhry S, Jacoby D, Moon JC, McKenna WJ. Update on hypertrophic cardiomyopathy and a guide to the guidelines. Nat Rev Cardiol. 2016;13:651–675. doi: 10.1038/nrcardio.2016.140.
195. Biagini E, Spirito P, Rocchi G, Ferlito M, Rosmini S, Lai F, Lorenzini M, Terzi F, Bacchi-Reggiani L, Boriani G, Branzi A, Boni L, Rapezzi C. Prognostic implications of the Doppler restrictive filling pattern in hypertrophic cardiomyopathy. Am J Cardiol. 2009;104:1727–1731. doi: 10.1016/j.amjcard.2009.07.057.
196. Braunwald E, Aygen MM. Idiopathic myocardial hypertrophy without congestive heart failure or obstruction to blood flow. Clinical, hemodynamic and angiocardiographic studies in fourteen patients. Am J Med. 1963;35:7–19.
197. Maron BJ, Rowin EJ, Maron MS, Braunwald E. Nonobstructive hypertrophic cardiomyopathy out of the shadows: known from the beginning but largely ignored … until now. Am J Med. 2017;130:119–123. doi: 10.1016/j.amjmed.2016.09.015.
198. Maron MS, Rowin EJ, Olivotto I, Casey SA, Arretini A, Tomberli B, Garberich RF, Link MS, Chan RH, Lesser JR, Maron BJ. Contemporary natural history and management of nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2016;67:1399–1409. doi: 10.1016/j.jacc.2016.01.023.
199. Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M, McKenna WJ. Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients. J Am Coll Cardiol. 2003;42:873–879.
200. Adabag AS, Casey SA, Kuskowski MA, Zenovich AG, Maron BJ. Spectrum and prognostic significance of arrhythmias on ambulatory Holter electrocardiogram in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005;45:697–704. doi: 10.1016/j.jacc.2004.11.043.
201. Elliott PM, Poloniecki J, Dickie S, Sharma S, Monserrat L, Varnava A, Mahon NG, McKenna WJ. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol. 2000;36:2212–2218.
202. Christiaans I, van Engelen K, van Langen IM, Birnie E, Bonsel GJ, Elliott PM, Wilde AA. Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy: systematic review of clinical risk markers. Europace. 2010;12:313–321. doi: 10.1093/europace/eup431.
203. O'Mahony C, Jichi F, Pavlou M, Monserrat L, Anastasakis A, Rapezzi C, Biagini E, Gimeno JR, Limongelli G, McKenna WJ, Omar RZ, Elliott PM; Hypertrophic Cardiomyopathy Outcomes Investigators. A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM risk-SCD). Eur Heart J. 2014;35:2010–2020. doi: 10.1093/eurheartj/eht439.
204. Nienaber CA, Hiller S, Spielmann RP, Geiger M, Kuck KH. Syncope in hypertrophic cardiomyopathy: multivariate analysis of prognostic determinants. J Am Coll Cardiol. 1990;15:948–955.
205. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation. 2001;104:2517–2524.
206. Siontis KC, Geske JB, Ong K, Nishimura RA, Ommen SR, Gersh BJ. Atrial fibrillation in hypertrophic cardiomyopathy: prevalence, clinical correlations, and mortality in a large high-risk population. J Am Heart Assoc. 2014;3:e001002. doi: 10.1161/JAHA.114.001002.
207. Debonnaire P, Joyce E, Hiemstra Y, Mertens BJ, Atsma DE, Schalij MJ, Bax JJ, Delgado V, Marsan NA. Left atrial size and function in hypertrophic cardiomyopathy patients and risk of new-onset atrial fibrillation. Circ Arrhythm Electrophysiol. 2017;10.
208. Guttmann OP, Rahman MS, O'Mahony C, Anastasakis A, Elliott PM. Atrial fibrillation and thromboembolism in patients with hypertrophic cardiomyopathy: systematic review. Heart. 2014;100:465–472. doi: 10.1136/heartjnl-2013-304276.
209. Eriksson MJ, Sonnenberg B, Woo A, Rakowski P, Parker TG, Wigle ED, Rakowski H. Long-term outcome in patients with apical hypertrophic cardiomyopathy. J Am Coll Cardiol. 2002;39:638–645.
210. Ho CY, McMurray JJV, Cirino AL, Colan SD, Day SM, Desai AS, Lipshultz SE, MacRae CA, Shi L, Solomon SD, Orav EJ, Braunwald E; for the VANISH trial investigators and executive committee. Valsartan for attenuating disease evolution in early sarcomeric hypertrophic cardiomyopathy: the design of the VANISH trial. Am Heart J. 2017;187:145–155. doi: 10.1016/j.ahj.2017.02.008.
211. Grazioli G, Usín D, Trucco E, Sanz M, Montserrat S, Vidal B, Gutierrez J, Canal R, Brugada J, Mont L, Sitges M. Differentiating hypertrophic cardiomyopathy from athlete's heart: an electrocardiographic and echocardiographic approach. J Electrocardiol. 2016;49:539–544. doi: 10.1016/j.jelectrocard.2016.03.005.
212. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006. Circulation. 2009;119:1085–1092. doi: 10.1161/CIRCULATIONAHA.108.804617.
213. Maron BJ, Shirani J, Poliac LC, Mathenge R, Roberts WC, Mueller FO. Sudden death in young competitive athletes. Clinical, demographic, and pathological profiles. JAMA. 1996;276:199–204.
214. Caselli S, Maron MS, Urbano-Moral JA, Pandian NG, Maron BJ, Pelliccia A. Differentiating left ventricular hypertrophy in athletes from that in patients with hypertrophic cardiomyopathy. Am J Cardiol. 2014;114:1383–1389. doi: 10.1016/j.amjcard.2014.07.070.
215. Butz T, van Buuren F, Mellwig KP, Langer C, Plehn G, Meissner A, Trappe HJ, Horstkotte D, Faber L. Two-dimensional strain analysis of the global and regional myocardial function for the differentiation of pathologic and physiologic left ventricular hypertrophy: a study in athletes and in patients with hypertrophic cardiomyopathy. Int J Cardiovasc Imaging. 2011;27:91–100. doi: 10.1007/s10554-010-9665-5.
216. Petersen SE, Selvanayagam JB, Francis JM, Myerson SG, Wiesmann F, Robson MD, Ostman-Smith I, Casadei B, Watkins H, Neubauer S. Differentiation of athlete's heart from pathological forms of cardiac hypertrophy by means of geometric indices derived from cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2005;7:551–558.
217. Sheikh N, Papadakis M, Ghani S, Zaidi A, Gati S, Adami PE, Carré F, Schnell F, Wilson M, Avila P, McKenna W, Sharma S. Comparison of electrocardiographic criteria for the detection of cardiac abnormalities in elite black and white athletes. Circulation. 2014;129:1637–1649. doi: 10.1161/CIRCULATIONAHA.113.006179.
218. Kadota C, Arimura T, Hayashi T, Naruse TK, Kawai S, Kimura A. Screening of sarcomere gene mutations in young athletes with abnormal findings in electrocardiography: identification of a MYH7 mutation and MYBPC3 mutations. J Hum Genet. 2015;60:641–645. doi: 10.1038/jhg.2015.81.
219. Bagnall RD, Weintraub RG, Ingles J, et al. A prospective study of sudden cardiac death among children and young adults. N Engl J Med. 2016;374:2441–2452. doi: 10.1056/NEJMoa1510687.
220. Maron BJ, Rowin EJ, Casey SA, Link MS, Lesser JR, Chan RH, Garberich RF, Udelson JE, Maron MS. Hypertrophic cardiomyopathy in adulthood associated with low cardiovascular mortality with contemporary management strategies. J Am Coll Cardiol. 2015;65:1915–1928. doi: 10.1016/j.jacc.2015.02.061.
221. Maron BJ, Ommen SR, Semsarian C, Spirito P, Olivotto I, Maron MS. Hypertrophic cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine. J Am Coll Cardiol. 2014;64:83–99. doi: 10.1016/j.jacc.2014.05.003.
222. Klarich KW, Attenhofer Jost CH, Binder J, Connolly HM, Scott CG, Freeman WK, Ackerman MJ, Nishimura RA, Tajik AJ, Ommen SR. Risk of death in long-term follow-up of patients with apical hypertrophic cardiomyopathy. Am J Cardiol. 2013;111:1784–1791. doi: 10.1016/j.amjcard.2013.02.040.
223. Wilcox WR, Banikazemi M, Guffon N, Waldek S, Lee P, Linthorst GE, Desnick RJ, Germain DP; International Fabry Disease Study Group. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am J Hum Genet. 2004;75:65–74. doi: 10.1086/422366.
224. Gruner C, Ivanov J, Care M, Williams L, Moravsky G, Yang H, Laczay B, Siminovitch K, Woo A, Rakowski H. Toronto hypertrophic cardiomyopathy genotype score for prediction of a positive genotype in hypertrophic cardiomyopathy. Circ Cardiovasc Genet. 2013;6:19–26. doi: 10.1161/CIRCGENETICS.112.963363.
225. Ho CY, Day SM, Colan SD, et al; HCMNet Investigators. The burden of early phenotypes and the influence of wall thickness in hypertrophic cardiomyopathy mutation carriers: findings from the HCMNet study. JAMA Cardiol. 2017;2:419–428. doi: 10.1001/jamacardio.2016.5670.
226. Nagueh SF, Bachinski LL, Meyer D, Hill R, Zoghbi WA, Tam JW, Quiñones MA, Roberts R, Marian AJ. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation. 2001;104: 128–130.
227. Harrison DC, Braunwald E, Glick G, Mason DT, Chidsey CA, Ross J, Jr. Effects of beta adrenergic blockade on the circulation with particular reference to observations in patients with hypertrophic subaortic stenosis. Circulation. 1964;29:84–98.
228. Cohen LS, Braunwald E. Chronic beta adrenergic receptor blockade in the treatment of idiopathic hypertrophic subaortic stenosis. Prog Cardiovasc Dis. 1968;11:211–221.
229. Nistri S, Olivotto I, Maron MS, Ferrantini C, Coppini R, Grifoni C, Baldini K, Sgalambro A, Cecchi F, Maron BJ. β Blockers for prevention of exercise-induced left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy. Am J Cardiol. 2012;110:715–719. doi: 10.1016/j.amjcard.2012.04.051.
230. Flamm MD, Harrison DC, Hancock EW. Muscular subaortic stenosis. Prevention of outflow obstruction with propranolol. Circulation. 1968;38:846–858.
231. Sherrid MV, Barac I, McKenna WJ, Elliott PM, Dickie S, Chojnowska L, Casey S, Maron BJ. Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005;45:1251–1258. doi: 10.1016/j.jacc.2005.01.012.
232. Gilligan DM, Chan WL, Joshi J, Clarke P, Fletcher A, Krikler S, Oakley CM. A double-blind, placebo-controlled crossover trial of nadolol and verapamil in mild and moderately symptomatic hypertrophic cardiomyopathy. J Am Coll Cardiol. 1993;21:1672–1679.
233. Spirito P, Autore C, Formisano F, et al. Risk of sudden death and outcome in patients with hypertrophic cardiomyopathy with benign presentation and without risk factors. Am J Cardiol. 2014;113:1550–1555. doi: 10.1016/j.amjcard.2014.01.435.
234. Maron BJ, Rowin EJ, Casey SA, Lesser JR, Garberich RF, McGriff DM, Maron MS. Hypertrophic cardiomyopathy in children, adolescents, and young adults associated with low cardiovascular mortality with contemporary management strategies. Circulation. 2016;133:62–73. doi: 10.1161/CIRCULATIONAHA.115.017633.
235. Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK, Daubert JP, Bardy GH, Favale S, Rea RF, Boriani G, Estes NA 3rd, Spirito P. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med. 2000;342:365–373. doi: 10.1056/NEJM200002103420601.
236. Maron BJ, Spirito P, Ackerman MJ, et al. Prevention of sudden cardiac death with implantable cardioverter-defibrillators in children and adolescents with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2013;61:1527–1535. doi: 10.1016/j.jacc.2013.01.037.
237. Maron BJ, Spirito P, Shen WK, et al. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA. 2007;298:405–412. doi: 10.1001/jama.298.4.405.
238. Vriesendorp PA, Schinkel AF, Van Cleemput J, Willems R, Jordaens LJ, Theuns DA, van Slegtenhorst MA, de Ravel TJ, ten Cate FJ, Michels M. Implantable cardioverter-defibrillators in hypertrophic cardiomyopathy: patient outcomes, rate of appropriate and inappropriate interventions, and complications. Am Heart J. 2013;166:496–502. doi: 10.1016/j.ahj.2013.06.009.
239. Nishimura RA, Seggewiss H, Schaff HV. Hypertrophic obstructive cardiomyopathy: surgical myectomy and septal ablation. Circ Res. 2017;121:771–783. doi: 10.1161/CIRCRESAHA.116.309348.
240. Lim DS, Lutucuta S, Bachireddy P, Youker K, Evans A, Entman M, Roberts R, Marian AJ. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation. 2001;103:789–791.
241. Tsybouleva N, Zhang L, Chen S, Patel R, Lutucuta S, Nemoto S, DeFreitas G, Entman M, Carabello BA, Roberts R, Marian AJ. Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy. Circulation. 2004;109:1284–1291. doi: 10.1161/01.CIR.0000121426.43044.2B.
242. Marian AJ, Senthil V, Chen SN, Lombardi R. Antifibrotic effects of antioxidant N-acetylcysteine in a mouse model of human hypertrophic cardiomyopathy mutation. J Am Coll Cardiol. 2006;47:827–834. doi: 10.1016/j.jacc.2005.10.041.
243. Shimada YJ, Passeri JJ, Baggish AL, O'Callaghan C, Lowry PA, Yannekis G, Abbara S, Ghoshhajra BB, Rothman RD, Ho CY, Januzzi JL, Seidman CE, Fifer MA. Effects of losartan on left ventricular hypertrophy and fibrosis in patients with nonobstructive hypertrophic cardiomyopathy. JACC Heart Fail. 2013;1:480–487. doi: 10.1016/j.jchf.2013.09.001.
244. Nagueh SF, Lombardi R, Tan Y, Wang J, Willerson JT, Marian AJ. Atorvastatin and cardiac hypertrophy and function in hypertrophic cardiomyopathy: a pilot study. Eur J Clin Invest. 2010;40:976–983. doi: 10.1111/j.1365-2362.2010.02349.x.
245. Mearini G, Stimpel D, Geertz B, et al. Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice. Nat Commun. 2014;5:5515. doi: 10.1038/ncomms6515.
246. Mearini G, Stimpel D, Krämer E, Geertz B, Braren I, Gedicke-Hornung C, Précigout G, Müller OJ, Katus HA, Eschenhagen T, Voit T, Garcia L, Lorain S, Carrier L. Repair of Mybpc3 mRNA by 5'-trans-splicing in a mouse model of hypertrophic cardiomyopathy. Mol Ther Nucleic Acids. 2013;2:e102. doi: 10.1038/mtna.2013.31.
247. Gedicke-Hornung C, Behrens-Gawlik V, Reischmann S, et al. Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice. EMBO Mol Med. 2013;5:1128–1145. doi: 10.1002/emmm.201202168.
248. Jiang J, Wakimoto H, Seidman JG, Seidman CE. Allele-specific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy. Science. 2013;342:111–114. doi: 10.1126/science.1236921.
249. Ho CY, Lakdawala NK, Cirino AL, Lipshultz SE, Sparks E, Abbasi SA, Kwong RY, Antman EM, Semsarian C, González A, López B, Diez J, Orav EJ, Colan SD, Seidman CE. Diltiazem treatment for preclinical hypertrophic cardiomyopathy sarcomere mutation carriers: a pilot randomized trial to modify disease expression. JACC Heart Fail. 2015;3:180–188. doi: 10.1016/j.jchf.2014.08.003.
250. Green EM, Wakimoto H, Anderson RL, et al. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science. 2016;351:617–621. doi: 10.1126/science.aad3456.